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PubMed2001

Saccadic eye movements are impaired in Duchenne muscular dystrophy.

Extraocular muscles are generally considered to be spared in Duchenne Muscular Dystrophy (DMD). However, this assumption is based mainly on clinical observations, as systematic eye movement recordings have been performed in a very limited number of cases. Our goal was to analyze several saccade parameters in a higher number of cases, in order to reveal a possible ocular-motor impairment in DMD. Data were collected from a population of 9 subjects with DMD and 9 healthy male subjects of comparable age as controls. We used the electrooculographic (EOG) technique coupled with advanced digital signal processing; saccade duration, amplitude, mean velocity, peak velocity and K factor (ratio mean/peak velocity) were measured. The DMD group showed saccades with significantly longer duration and lower velocity, with respect to controls; these differences were accounted for mainly by the largest movements, whereas there were no significant differences at the smallest eccentricity tested (3 deg). Neither amplitude nor K factor were significantly different from controls for any of the eccentricities tested. To our knowledge. this is the first study to suggest significant impairment of eye movements in Duchenne muscular dystrophy.

Adolescent↗
PubMedDate not supplied

Long-range restriction map around the Duchenne muscular dystrophy gene.

Duchenne muscular dystrophy is an X-linked recessive disease affecting about 1 in 4,000 newborn boys. As in many other inherited diseases, the biochemical basis of the condition is unknown, and as yet there is no effective treatment. Translocations, deletions and other mutations leading to the DMD phenotype are distributed over a chromosomal area of large, but unknown size. Using pulsed-field gradient gel electrophoresis, we have now determined restriction maps of a major fraction of this area, covering two regions of three million basepairs in total, and used it to determine the position of several probes linked to DMD. The maps establish physical distances between structural changes associated with the DMD phenotype and provide evidence for a CpG-rich island proximal to the area containing translocations and deletions associated with the DMD phenotype.

Chromosome Deletion↗
PubMedDate not supplied

The mapping of a cDNA from the human X-linked Duchenne muscular dystrophy gene to the mouse X chromosome.

The recent discovery of sequences at the site of the Duchenne muscular dystrophy (DMD) gene in humans has opened up the possibility of a detailed molecular analysis of the genes in humans and in related mammalian species. Until relatively recently, there was no obvious mouse model of this genetic disease for the development of therapeutic strategies. The identification of a mouse X-linked mutant showing muscular dystrophy, mdx, has provided a candidate mouse genetic homologue to the DMD locus; the relatively mild pathological features of mdx suggest it may have more in common with mutations of the Becker muscular dystrophy type at the same human locus, however. But the close genetic linkage of mdx to G6PD and Hprt on the mouse X chromosome, coupled with its comparatively mild pathology, have suggested that the mdx mutation may instead correspond to Emery Dreifuss muscular dystrophy which itself is closely linked to DNA markers at Xq28-qter in the region of G6PD on the human X chromosome. Using an interspecific mouse domesticus/spretus cross, segregating for a variety of markers on the mouse X chromosome, we have positioned on the mouse X chromosome sequences homologous to a DMD cDNA clone. These sequences map provocatively close to the mdx mutation and unexpectedly distant from sparse fur, spf, the mouse homologue of OTC (ornithine transcarbamylase) which is closely linked to DMD on the human X chromosome.

Alleles↗
PubMedDate not supplied

Direct detection of more than 50% of the Duchenne muscular dystrophy mutations by field inversion gels.

Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting about 1 in 3,500 males. It is allelic with the milder Becker muscular dystrophy. The biochemical basis for both diseases is unknown and no effective treatment is available. Long-range physical mapping has shown that the DMD gene, localized in Xp21, is extremely large, exceeding 2 million base pairs. Until now, carrier detection and prenatal diagnosis has involved the use of linked restriction fragment length polymorphism markers which detect muscular dystrophy-associated deletions in about 10% of the cases. Field inversion gel electrophoresis (FIGE) allows the detection of structural rearrangements in 21 out of 39 of the DMD patients studied (54%), of which 14 (65%) were not detected by conventional methods. Large deletions seem to make up a much higher fraction of the DMD mutations than so far indicated by other methods. A region prone to deletion was located in the distal half of the gene. FIGE analysis could provide a valuable extension of information for carrier detection and prenatal diagnosis. The technique should be generally applicable to the study of diseases involving structural chromosomal rearrangements.

Alleles↗
PubMed1988

Expression of the putative Duchenne muscular dystrophy gene in differentiated myogenic cell cultures and in the brain.

Duchenne muscular dystrophy (DMD), a sex-linked degenerative disorder of the muscle, is one of the most common lethal genetic diseases in man. It affects about one male in 3,500, with an estimated one-third of cases being caused by new mutations. A less severe disease, Becker's muscular dystrophy (BMD), maps to the same chromosomal locus and is most probably an allelic form of DMD. Both diseases are sometimes associated with various degrees of mental retardation; the molecular basis of these phenotypes is unknown (for review, see ref. 1). The giant DMD gene spans approximately 2,000 kilobases (kb) (0.05% of the human genome) and encodes a 14-kb mRNA. The tissue-specificity of its expression has not been precisely determined. Monaco et al., using Northern blots, reported expression of the gene in human fetal skeletal muscle and small intestine but not in human fetal brain, or in human cultured myoblasts and transformed B and T cells. More recently, expression was detected in mouse skeletal and cardiac muscle, but not in mouse brain. Here we show, using a ribonuclease protection assay, that the DMD gene is developmentally regulated in rat and mouse myogenic cell cultures, and that it is expressed in rat and mouse striated muscle, in mouse smooth muscle and in rat, mouse and rabbit brain. We could not detect transcripts in other non-muscle tissues.

Amino Acid Sequence↗
PubMed1990

Very mild muscular dystrophy associated with the deletion of 46% of dystrophin.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), a much milder form of the disease where the age of onset can sometimes be as late as the third or fourth decade of life, are caused by mutations in the same X-linked gene, a 14 kilobase (kb) transcript which is spread over more than 2 megabases of the human X chromosome. The corresponding protein, dystrophin, has a relative molecular mass of 400,000. Most mutations causing DMD and BMD are deletions and deletions associated with both phenotypes are observed throughout the gene sequence. This observation led to the suggestion that DMD patients possess deletions that disrupt the reading frame of the protein, whereas BMD patients have deletions that retain the translational reading frame and enable the muscle cells to produce altered dystrophin products. This theory is supported by immunoblotting studies, which show that DMD patients lack dystrophin in their muscle cells or that dystrophin is present at very low levels, whereas BMD patients produce a protein with reduced abundance or abnormal size. Here we describe a deletion of the dystrophin gene in a family segregating for very mild BMD, one member of which was still ambulant at age 61 years, which removes a central part of the dystrophin gene encompassing 5,106 base pairs of coding sequence, almost half the coding information. Immunological analysis of muscle from one of the patients demonstrates that this mutation results in the production of a truncated polypeptide localized correctly in the muscle cell. These results are particularly significant in the context of gene therapy which, if it is ever envisaged, would be facilitated by the replacement of the very large dystrophin gene with a more manipulatable mini-gene construct.

Blotting, Western↗
PubMed1991

Expression of recombinant dystrophin and its localization to the cell membrane.

Duchenne's muscular dystrophy (DMD) is an X-linked progressive myopathy caused by a defect in the DMD gene locus. The gene corresponding to the DMD locus produces a 14-kilobase (kb) messenger RNA that codes for a large cytoskeletal membrane protein, dystrophin. DMD and Becker's muscular dystrophy are the consequences of dystrophin mutations. The exact biological function of dystrophin remains unknown but it has been demonstrated that it is localized to the cytoplasmic face of the cell membrane and has direct interaction with several other membrane proteins. We report here the synthesis of a 14-kb full-length complementary DNA for the mouse muscle dystrophin mRNA and the expression of this cDNA in COS cells. The recombinant dystrophin is indistinguishable from mouse muscle dystrophin by western blot analysis with anti-dystrophin antibodies and was shown by an immunofluorescent technique to be localized in the cell membrane. Our successful construction of a functional full-length cDNA opens opportunities for the study of structure and function of dystrophin and provides an opportunity to initiate gene therapy studies.

Animals↗
PubMed1992

Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy.

X-linked recessive Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a membrane cytoskeletal protein. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoprotein. The dystrophin-glycoprotein complex has been proposed to span the sarcolemma to provide a link between the subsarcolemmal cytoskeleton and the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a large reduction in all of the dystrophin-associated protein. We have investigated the possibility that a deficiency of a dystrophin-associated protein could be the cause of severe childhood autosomal recessive muscular dystrophy (SCARMD) with a DMD-like phenotype. Here we report the specific deficiency of the 50K dystrophin-associated glycoprotein (M(r) 50,000) in sarcolemma of SCARMD patients. Therefore, the loss of this glycoprotein is a common denominator of the pathological process leading to muscle cell necrosis in two forms of muscular dystrophy, DMD and SCARMD.

Biopsy↗
PubMed1993

Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity.

Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked recessive diseases caused by defective expression of dystrophin. The mdx mouse, an animal model for DMD, has a mutation that eliminates expression of the 427K muscle and brain isoforms of dystrophin. Although these animals do not display overt muscle weakness or impaired movement, the diaphragm muscle of the mdx mouse is severely affected and shows progressive myofibre degeneration and fibrosis which closely resembles the human disease. Here we explore the feasibility of gene therapy for DMD by examining the potential of a full-length dystrophin transgene to correct dystrophic symptoms in mdx mice. We find that expression of dystrophin in muscles of transgenic mdx mice eliminates the morphological and immunohistological symptoms of muscular dystrophy. In addition, overexpression of dystrophin prevents the development of the abnormal mechanical properties associated with dystrophic muscle without causing deleterious side effects. Our results provide functional evidence for the feasibility of gene therapy for DMD.

Animals↗
PubMed2001

Regulation of DNA methylation of Rasgrf1.

In mammals, DNA is methylated at cytosines within CpG dinucleotides. Properly regulated methylation is crucial for normal development. Inappropriate methylation may contribute to tumorigenesis by silencing tumor-suppressor genes or by activating growth-stimulating genes. Although many genes have been identified that acquire methylation and whose expression is methylation-sensitive, little is known about how DNA methylation is controlled. We have identified a DNA sequence that regulates establishment of DNA methylation in the male germ line at Rasgrf1. In mice, the imprinted Rasgrf1 locus is methylated on the paternal allele within a differentially methylated domain (DMD) 30 kbp 5' of the promoter. Expression is exclusively from the paternal allele in neonatal brain. Methylation is regulated by a repeated sequence, consisting of a 41-mer repeated 40 times, found immediately 3' of the DMD. This sequence is present in organisms in which Rasgrf1 is imprinted. In addition, DMD methylation is required for imprinted Rasgrf1 expression. Together the DMD and repeat element constitute a binary switch that regulates imprinting at the locus.

Alleles↗
PubMed2003

Pharmacological strategies for muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal, genetic disorder whose relentless progression underscores the urgency for developing a cure. Although Duchenne initiated clinical trials roughly 150 years ago, therapies for DMD remain supportive rather than curative. A paradigm shift towards developing rational therapeutic strategies occurred with identification of the DMD gene. Gene- and cell-based therapies designed to replace the missing gene and/or dystrophin protein have achieved varying degrees of success. However, pharmacological strategies not designed to replace dystrophin per se appear promising, and can circumvent many hurdles hampering gene- and cell-based therapy. Here, we will review present pharmacological strategies, in particular those dealing with functional substitution of dystrophin by utrophin and enhancing muscle progenitor commitment by myostatin blockade, with a view toward facilitating drug discovery for DMD.

Animals↗
PubMed2026

Integrative multi-omics analysis reveals lipid/metabolite dysregulation and temporal decoupling in disease progression.

Our study presents and applies a metabolomics-driven multi-omics integration strategy to elucidate dynamic pathway interactions during disease progression. We analyzed longitudinal metabolomics datasets from a Duchenne muscular dystrophy (DMD) mouse model (6-30 weeks) and an acute Bothrops asper envenomation model (1-24 h) to contrast chronic versus acute inflammation. In the DMD model, we predicted phased cross-talk between sphingolipid metabolism and neurotrophin signaling: an early proteomic surge followed by lipid-mediated amplification and a late convergence at the protein level. Arginine and proline metabolism exhibited early metabolite accumulation preceding delayed inferred protein changes, consistent with impaired nitric oxide synthesis and argininemia-like effect. We also predicted late-stage activation of the AGE-RAGE pathway in DMD, likely triggered by ceramide buildup, and an autophagy-related lipid metabolic shift at mid-stage. In the envenomation model, tryptophan-kynurenine and nicotinamide pathways for NAD⁺ biosynthesis were rapidly perturbed at the metabolite level (1-3 h) but induced corresponding predicted enzymes only by 24 h. Thyroid hormone signaling showed an early coupling of substrate availability (tyrosine surge at 1 h) with predicted stress-response proteins and a second, delayed wave of inferred transcriptional regulators at 24 h. Acute envenomation also triggered immediate glycine/serine utilization possibly for antioxidant defense and glycerophospholipid breakdown (via phospholipase A₂), whereas chronic DMD showed sustained glycine/serine engagement and inferred, unresolved phospholipid perturbation without protein-level compensation, which may result from chronic oxidative stress. Overall, our integrative analysis revealed time-specific, multi-layer molecular perturbations distinguishing acute toxin injury from chronic muscle degeneration. Key metabolic control points (ceramide accumulation, arginine flux diversion, autophagy-lipid cross-talk, NAD⁺ salvage timing) were identified, highlighting potential targets for stage-specific therapeutic or nutritional interventions.

Animals↗
PubMed2004

Normal mode analysis using the driven molecular dynamics method. II. An application to biological macromolecules.

The driven molecular-dynamics (DMD) method, recently proposed by Bowman, Zhang, and Brown [J. Chem. Phys. 119, 646 (2003)], has been implemented into the TINKER molecular modeling program package. The DMD method yields frequencies and normal modes without evaluation of the Hessian matrix. It employs an external harmonic driving term that can be used to scan the spectrum and determine resonant absorptions. The molecular motions, induced by driving at resonant frequencies, correspond to the normal-mode vibrations. In the current work we apply the method to a 20-residue protein, Trp-cage, that has been reported by Neidigh, Fesinmeyer, and Andersen [Nature Struct. Biol. 9, 425 (2002)]. The structural and dynamical properties of this molecule, such as B-factors, root-mean square fluctuations, anisotropies, vibrational entropy, and cross-correlations coefficients, are calculated using the DMD method. The results are in very good agreement with ones calculated using standard normal-mode analysis method. Thus, the DMD method provides a viable alternative to the standard Hessian-based method and has considerable potential for the study of large systems, where the Hessian-based method is not feasible.

Algorithms↗
PubMed2002

Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice.

Duchenne muscular dystrophy (DMD) is a congenital X-linked myopathy caused by lack of dystrophin protein expression. In DMD, the expression of many dystrophin-associated proteins (DAPs) is reduced along the sarcolemmal membrane, but the same proteins remain concentrated at the neuromuscular junction where utrophin, a dystrophin homologue, is expressed [Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, K. D. & Campbell, K. (1992) Nature (London) 360, 588-591]. This outcome has led to the concept that ectopic expression of a "synaptic scaffold" of DAPs and utrophin along myofibers might compensate for the molecular defects in DMD. Here we show that transgenic overexpression of the synaptic CT GalNAc transferase in the skeletal muscles of mdx animals (mdx/CT) increases the expression of utrophin and many DAPs, including dystroglycans, sarcoglycans, and dystrobrevins, along myofibers. Protein expression of utrophin and DAPs was equal to or above that of wild-type mice. In addition, alpha-dystroglycan was glycosylated with the CT carbohydrate antigen in mdx/CT but not in mdx muscles. mdx/CT mice have little or no evidence of muscular dystrophy by several standard measures; Serum creatine kinase levels, percentage of centrally located myofiber nuclei, and variance in myofiber diameter in mdx/CT muscles were dramatically reduced compared with mdx mice. These data suggest that ectopic expression of the CT GalNAc transferase creates a functional dystrophin-related complex along myofibers in the absence of dystrophin and should be considered as a target for therapeutic intervention in DMD.

Animals↗
PubMed2000

Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype.

It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expression in their skeletal muscle. However, it remains unknown whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of DMD. Here, using a genetic approach, we test this hypothesis directly by overexpressing wild-type caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3- overexpressing transgenic mice reveals: (i) a dramatic increase in the number of sarcolemmal muscle cell caveolae; (ii) a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and (iii) down-regulation of dystrophin and beta-dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase levels, consistent with the myo-necrosis observed morphologically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans.

Animals↗
PubMed2000

Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model.

Duchenne muscular dystrophy (DMD) is the most common and lethal genetic muscle disorder, caused by recessive mutations in the dystrophin gene. One of every 3,500 males suffers from DMD, yet no treatment is currently available. Genetic therapeutic approaches, using primarily myoblast transplantation and adenovirus-mediated gene transfer, have met with limited success. Adeno-associated virus (AAV) vectors, although proven superior for muscle gene transfer, are too small (5 kb) to package the 14-kb dystrophin cDNA. Here we have created a series of minidystrophin genes (<4.2 kb) under the control of a muscle-specific promoter that readily package into AAV vectors. When injected into the muscle of mdx mice (a DMD model), two of the minigenes resulted in efficient and stable expression in a majority of the myofibers, restoring the missing dystrophin and dystrophin-associated protein complexes onto the plasma membrane. More importantly, this AAV treatment ameliorated dystrophic pathology in mdx muscle and led to normal myofiber morphology, histology, and cell membrane integrity. Thus, we have defined minimal functional dystrophin units and demonstrated the effectiveness of using AAV to deliver the minigenes in vivo, offering a promising avenue for DMD gene therapy.

Animals↗
PubMed2000

Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to alpha-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD.

Adolescent↗
PubMed1983

Increased membrane permeability to chloride in Duchenne muscular dystrophy fibroblasts and its relationship to muscle function.

Previous studies have suggested an abnormality in Cl- metabolism in Duchenne muscular dystrophy (DMD) fibroblasts. In order to further characterize this abnormality, we have studied 36Cl- distribution and permeability in 11 DMD and 12 normal fibroblast lines. Under steady-state conditions Cl- efflux in fibroblasts is observed to be biphasic, revealing the presence of two major subcellular compartments. Each compartment contains approximately half of the cellular Cl-. The faster of the two observed efflux components is significantly higher in DMD than in control fibroblasts (P less than 0.001). To determine the results of a similar increase in Cl- permeability on skeletal muscle action potentials, we have simulated the effects of increased Cl- conductance on muscle by using a computer model. Effects on the simulated action potential include lower rates of membrane depolarization, lower overpotential, longer duration, and lower input resistance. These effects are similar to those actually observed in DMD muscle.

Action Potentials↗